In males, small amounts of estrogen are produced by aromatization of testosterone both in the testes and peripheral tissues. Although present in only small amounts, generally less than one-fourth to one-tenth that in premenopausal women, estrogen may play a role in the regulation of the male hypothalamic pituitary gonadaxis, bone development, development of the prostate and metabolic function. In the hypothalamus, conversion of testosterone to estrogen results in negative feedback on gonadotropin releasing hormone and subsequent gonadotropin release. Estrogens thus normally reduce circulating testosterone and anti-estrogens result in corresponding increases. As men age, the proportion of fat to lean tissue gradually increases. Aromatization of testosterone in fat may lead to gradually increased estrogen to testosterone ratios and negative feedback that reduces total testosterone levels.
Hypogonadism is recognized as a common occurrence in older males. A number of studies have suggested that hypogonadism may result in some of the observed decrements in muscle and skeletal mass associated with advancing age. Recent studies have suggested that androgen therapy produces a small but significant improvement in muscle strength in eugonadal males. Testosterone deficiency has been associated with hip fracture, and bone mass has been correlated with testosterone levels in older persons.
Males who received testosterone had a significant increase in bioavailable testosterone concentration, hematocrit, right hand muscle strength and osteocalcin concentration. They had a decrease in cholesterol (without a change in HDL-cholesterol) levels and decreased BUN/Creatinine ratios. Morley, et al. JAGS 41:149-152 (1993).
The estrogen antagonist tamoxifen has been used in males to treat advansced breast cancer. Treatment with tamoxifen has been shown to increase serum levels of testosterone in both mammal and oligozoospermic men. (Lewis-Jones, et al., andrologia 19 (1):86-90 (1987)). In addition, the anti-estrogen clomiphene is used to treat decreased libido, hypogonadotrophic hypogonadism and associated infertility. A potential role for anti-estrogens in the older male has not been systematically evaluated.
Droloxifene (Formula I, below, R.sup.1, R.sup.2 =methyl) is a new tissue-specific estrogen agonist/antagonist that is being developed for the treatment of advanced breast cancer and osteoporosis. Although droloxifene has been studied in a few men with advanced colon or pancreatic cancer, its endocrine effects in the normal male have not been studied. Droloxifene is chemically related to tamoxifen, but in preclinical studies in rats is devoid of tamoxifen's hepatocarcinogicity. In humans, droloxifene has a superior pharmacokinetic profile with fewer, inactive, metabolites a shorter half life of 24 hours (vs. tamoxifen's 1 to 2 weeks and multiple metabolites).